THE CLINICAL IMPORTANCE OF TOTAL DRUG MONITORING IN REDUCING THE TOXICITY ASSOCIATED WITH VALPROIC ACID IN EPILEPTIC CHILDREN IN TAIF CITY
Main Article Content
Keywords
TDM, Valproic acid, Toxicity, Liver injury
Abstract
Background: Epilepsy is a group of neurological disorders that are characterized by an epileptic seizure. An epileptic seizure can last for seconds and may last for a longer time of fewer than five minutes. An epileptic seizure may cause physical harm; therefore, its management is necessary. Epilepsy requires long-term epileptic treatment. Children with epilepsy can be managed by valproic acid, which is the very commonly used antiepileptic drug in clinical practice. However, chronic usage of valproic acid is associated with adverse effects, especially among children. These adverse effects involve hepatotoxicity, coagulation disorders, and pancreatitis. Therapeutic drug monitoring (TDM) is effective in adjusting the dosage of the drug to obtain the optimum concentration in order to reduce toxicities associated with the medication.
Aim: To investigate the effects of TDM in assessing liver injury associated with valproic acid treatment for epileptic children .
Methods: This study is a cohort study that was conducted on epileptic children treated with valproic acid monotherapy at least one month after using TDM at the children hospital in Taif. Liver enzymes, serum creatinine, total bilirubin, direct bilirubin, and dose of valproic acid adjusted by TDM were estimated. Statistical analysis was performed using SPSS software version 21.
Results: A total of 126 epileptic children were involved in our study; 68 were involved in the TDM group, and 58 were involved in the non-TDM group. There were significant differences between the two groups regarding the mean of AST (P=0.0001), ALT (P=0.048), and total bilirubin (P=0.0001). There was a significant negative association between valproic acid levels determined by TDM and ALT (r=-0.256, P=0.035), whereas the correlation was positive with serum creatinine (r=0.414, P=0.0001). Logistic regression model showed significant association between TDM usage and elevated AST, OR=0.033, 95% CI=0.004-0.2 (P=0.001).
Conclusion: TDM has a significant impact in reducing liver injury and maintaining good hepatic function among epileptic children treated with valproic acid. TDM is also can be used to monitor renal function and correct renal injury by adjusting the valproic acid dose.
References
2. Al-Roubaie Z, Guadagno E, Ramanakumar AV, Khan AQ, and Myers KA. (2020). Clinical utility of therapeutic drug monitoring of antiepileptic drugs: Systematic review. Neurology: Clinical Practice;10(4), pp.344-355.
3. Alaqeel, A. and Sabbagh, A.J. (2013). Epilepsy; what do Saudi's living in Riyadh know?. Seizure, 22(3), pp.205-209.
4. Alonazi NA, Alnemri A, El Melegy E, Mohamed N, Talaat I, Hosny A, Alonazi A, Mohamed S. (2018). Clinical characteristics and aetiology of early childhood epilepsy: a single centre experience in Saudi Arabia. Sudan J Paediatr;18(1):57-62.
5. Alsharif, M.M., El-Fetoh, N.M.A., Ali, G.Y., Alanazi, K.F., Alanazi, A.N., FalahAlanazi, O., Alshalan, M.H., Alfuhigi, Z.D., Alruwaili, A.E., Alhazmi, R.S. and Alruwaili, A.S.M. (2017). Epilepsy as a health problem among school children in Turaif, Northern Saudi Arabia, 2017. Electronic physician, 9(8), p.5036.
6. Annegers JF. (1994). Epidemiology and genetics of epilepsy. Neurol Clin; 12: 15-29. Batalden PB, Van Dyne BJ, Cloyd J.(1979). Pancreatitis associated with valproic acid therapy. Pediatrics ; 64 : 520 -2
7. Birbeck, G.L. (2010). Epilepsy care in developing countries: part I of II. Epilepsy currents, 10(4), pp.75-79.
8. Birkett DJ. (1997). Pharmacokinetics made easy: therapeutic drug monitoring. Aust Prescr;20:9-11.
9. Biton V, Mirza W, Montouris G, Vuong A. (2001). Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology;56:172–7. Bombardieri R, Pinci M, Moavero R, Cerminara C, Curatolo P. (2010). Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. Eur J Paediatr Neurol ; 14: 146-149.
10. Bryant, A.E., III; Dreifuss, F.E. (1996). Valproic acid hepatic fatalities. III. U.S. experience since 1986. Neurology; 46(2), 465-469.
11. Canpolat, M., Kumandas, S., Poyrazoglu, H.G., Gumus, H., Elmali, F. and Per, H. (2014). Prevalence and risk factors of epilepsy among school children in Kayseri City Center, an urban area in Central Anatolia, Turkey. Seizure, 23(9), pp.708-716.
12. Chateauvieux, S., Morceau, F., Dicato, M. and Diederich, M. (2010). Molecular and therapeutic potential and toxicity of valproic acid. Journal of Biomedicine and Biotechnology, 2010.
13. Chen, Z., Brodie, M.J., Liew, D. and Kwan, P. (2018). Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30year longitudinal cohort study. JAMA neurology, 75(3), pp.279-286.
14. Christianson AL, Zwane ME, Manga P, Rosen E, Venter A, Kromberg JG. (2000). Epilepsy in rural South Africa childrenprevalence, associated disability and management. S Afr Med J;90:262-6.
15. Claassen J, Riviello JJ, Silbergleit R. (2015). Emergency Neurological Life Support: Status Epilepticus. Neurocrit Care;23 Suppl 2:S136-42.
16. Corman CL, Leung NM, Guberman AH. (1997). Weight gain in epileptic patients during treatment with valproic acid: a retrospective study. Can J Neurol Sci;24:240–4. Davis, R.; Peters, D.H.; McTavish, D. Valproic acid. (1994). A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs; 47(2), 332-372.
17. Develioglu, H., Özgören, Ö., Nalbantoglu, M., Eren, K. and Göze, F. (2008). Histopathological evaluation of drug allergy observed with gingival overgrowth induced by phenytoin: A case report. Balkan Journal of Stomatology, 12(3), pp.166-169.
18. Dreifuss, F.E., Santilli, N., Langer, D.H., Sweeney, K.P., Moline, K.A. and Menander, K.B. (1987). Valproic acid hepatic fatalities: a retrospective review. Neurology, 37(3), pp.379-379.
19. Eilers R. (1995). Therapeutic drug monitoring for the treatment of psychiatric disorders. Clinical use and cost effectiveness. Clin Pharmacokinet; 29:442-450.
20. Elger, C.E. and Hoppe, C. (2018). Diagnostic challenges in epilepsy: seizure underreporting and seizure detection. The Lancet Neurology, 17(3), pp.279-288.
21. El-Hazmi MAF, Warsy AS. (1996). Genetic disorders among Arab populations. Saudi Med J; 17: 108-123.
22. Esfahani, P.N., Nasiri, J., Badihian, S. and Yaghini, O. (2019). Short-term side effects of low dose valproate monotherapy in epileptic children: a prospective study. Iranian Journal of Child Neurology, 13(2), p.37.
23. Espinosa PS, Salazar JC, Yu L, Baumann RJ. (2008). Lack of valproic acid-associated weight gain in prepubertal children. Pediatr Neurol;39:177–80.
24. Evans WE, Schentag JJ, Jasko WJ. (1992). Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. 3rd ed. Lippincott Williams & Wilkins.
25. Farghaly, W.M., Abd Elhamed, M.A., Hassan, E.M., Soliman, W.T., Yhia, M.A. and Hamdy, N.A. (2018). Prevalence of childhood and adolescence epilepsy in Upper Egypt (desert areas). The Egyptian journal of neurology, psychiatry and neurosurgery, 54(1), pp.1-7.
26. Fattore C, Messina S, Battino D, Croci D, Mamoli D, Perucca E. (2006). The influence of old age and enzyme inducing comedication on the pharmacokinetics of valproic acid at steady-state: A case-matched evaluation based on therapeutic drug monitoring data. Epilepsy Res 2006; 70:153-160.
27. Gerstner, T., Bell, N. and König, S. (2008). Oral valproic acid for epilepsy-long-term experience in therapy and side effects. Expert opinion on pharmacotherapy, 9(2), pp.285292.
28. Gerstner, T., Teich, M., Bell, N., Longin, E., Dempfle, C.E., Brand, J. and König, S. (2006). Valproate‐associated coagulopathies are frequent and variable in children. Epilepsia, 47(7), pp.1136-1143.
29. Giussani G., Cricelli C., Mazzoleni F., Cricelli I., Pasqua A., Pecchioli S., Lapi F., Beghi E. (2014). Prevalence and incidence of epilepsy in Italy based on a nationwide database. Neuroepidemiology; 43:228–232.
30. Glauser, T., Ben‐Menachem, E., Bourgeois, B., Cnaan, A., Guerreiro, C., Kälviäinen, R., Mattson, R., French, J.A., Perucca, E., Tomson, T. and ILAE Subcommission on AED Guidelines. (2013). Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia, 54(3), pp.551-563.
31. Glauser, T.; Ben-Menachem, E.; Bourgeois, B.; Cnaan, A.; Guerreiro, C.; Kälviäinen, R.; Mattson, R.; French, J.A.; Perucca, E.; Tomson, T. (2013). Guidelines, I.S.A. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia, 54(3), 551- 563.
32. Guerrini, R. (2006). Valproate as a mainstay of therapy for pediatric epilepsy. Paediatr. Drugs, 8(2), 113-129
33. Guo CY, Ronen GM, Atkinson SA. (2001). Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia 2001;42:1141–7.
34. Hamdy, N.A., Alamgir, M.J., El Gamri, E.M., Khedr, M.H. and Fazili, S. (2014). Profile of epilepsy in a regional hospital in Al qassim, Saudi Arabia. International journal of health sciences, 8(3):247.
35. Horaib, W., Alshamsi, R., Zabeeri, N., Al-Baradie, R.S. and Wahab, M.M.A. (2021). Quality of Life and the Perceived Impact of Epilepsy in Children and Adolescents in the Eastern Province of the Kingdom of Saudi Arabia. Cureus,13(12).
36. Houben ML, Wilting I, Stroink H, van Dijken PJ. (2005). Pancreatitis, complicated by a pancreatic pseudocyst associated with the use of valproic acid. Eur J Paediatr Neurol; 9 : 77 -80
37. Huff JS, Fountain NB. (2011). Pathophysiology and definitions of seizures and status epilepticus. Emerg. Med. Clin. North Am;29(1):1-13.
38. Huseyinoglu N, Ozben S, Arhan E, Palanci Y, Gunes N. (2012). Prevalence and risk factors of epilepsy among school children in eastern Turkey. Pediatr Neurol; 47(1): 13-8. Indrayati, L., Nur, F.T. and Soebagyo, B. (2020). Platelet counts in epileptic children receiving valproic acid. Paediatrica Indonesiana, 60(1), pp.13-7.
39. Jobst, B.C., Siegel, A.M., Thadani, V.M., Roberts, D.W., Rhodes, H.C. and Williamson, P.D. (2000). Intractable seizures of frontal lobe origin: clinical characteristics, localizing signs, and results of surgery. Epilepsia, 41(9):1139-1152.
40. Johannessen Landmark, C., Johannessen, S.I. and Patsalos, P.N. (2020). Therapeutic drug monitoring of antiepileptic drugs: current status and future prospects. Expert Opinion on Drug Metabolism & Toxicology, 16(3), pp.227-238.
41. Kang, J.S. and Lee, M.H. (2009). Overview of therapeutic drug monitoring. The Korean journal of internal medicine, 24(1), p.1.
42. Kerr, C., Nixon, A. and Angalakuditi, M. (2011). The impact of epilepsy on children and adult patients’ lives: development of a conceptual model from qualitative literature. Seizure, 20(10), pp.764-774.
43. Koenig, S.A., Buesing, D., Longin, E., Oehring, R., Häussermann, P., Kluger, G., Lindmayer, F., Hanusch, R., Degen, I., Kuhn, H. and Samii, K. (2006). Valproic acid–induced Hepatopathy: nine new fatalities in Germany from 1994 to 2003. Epilepsia, 47(12), pp.2027-2031.
44. Krasowski, M.D. (2010). Therapeutic drug monitoring of the newer anti-epilepsy medications. Pharmaceuticals, 3(6), pp.1909-1935.
45. Kumar, S.V., Radhika, Y. and Kumar, G.V. (2011). Therapeutic drug monitoring of valproic acid in pediatric epileptic patients. Int Bull Drug Res, 1, pp.11-18.
46. Kwan P, Brodie MJ. (2000). Early identification of refractory epilepsy. N Engl J Med;342:314–319
47. Landmark, C.J., Johannessen, S.I. and Tomson, T. (2016). Dosing strategies for antiepileptic drugs: from a standard dose for all to individualised treatment by implementation of therapeutic drug monitoring. Epileptic Disorders, 18(4), pp.367-383.
48. Lee GP. (2010). Neuropsychology of Epilepsy and Epilepsy Surgery. 1st edition . Oxford University Press, Oxford, UK; 2010. https://global.oup.com/academic/product/neuropsy chology-of-epilepsy-and-epilepsysurgery- 9780195372502?cc=in&lang=en&.
49. Lee J. (2019). Antiepileptic drugs in children: current concept. J Korean Neurosurg Soc;62:296–301.
50. Longin E, Teich M, Koelfen W, Koenig SA.(2002). Topiramate enhances the risk of valproate associated side effects in three children. Epilepsia; 43 : 451 -4
51. Löscher, W. (2002). Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs;16(10), 669-694.
52. Lv R.J., Wang Q., Cui T., Zhu F., Shao X.Q. (2017). Status epilepticus-related etiology, incidence, and mortality: A meta-analysis. Epilepsy Res; 136:12–17.
53. Mac TL, Tran DS, Quet F, Odermatt P, Preux PM, Tan CT. (2007). Epidemiology, etiology, and clinical management of epilepsy in Asia: a systematic review. Lancet Neurol; 6:533–543.
54. Magazi D S, Nkohla S, & Mmako M T. (2018). Epilepsy seizure types, classification and treatment. South African Family Practice, 60(4), 22-27.
55. Maheshwari, M.C.; Jeavons, P.M. (1975). Proceedings: The effect of sodium valproate (Epilim) on the EEG. Electroencephalogr. Clin. Neurophysiol, 39(4), 429.
56. Maksoud, H.M.A., El-Shazly, S.M. and El Saied, M.H. (2016). Effect of antiepileptic drug (valproic acid) on children growth. Egyptian Pediatric Association Gazette, 64(2), pp.69-73.
57. Maksoud, H.M.A., El-Shazly, S.M. and El Saied, M.H. (2016). Effect of antiepileptic drug (valproic acid) on children growth. Egyptian Pediatric Association Gazette, 64(2), pp.69-73.
58. McLane, H.C., Berkowitz, A.L., Patenaude, B.N., McKenzie, E.D., Wolper, E., Wahlster, S., Fink, G. and Mateen, F.J. (2015). Availability, accessibility, and affordability of neurodiagnostic tests in 37 countries. Neurology, 85(18), pp.1614-1622.
59. Mehndiratta, M.M., Thomas, S.V., Baheti, N.N., Bansal, A.R., Bhoi, S., Dubey, D., Gulati, S., Jain, S., Jayalakshmi, S., Kalita, J. and Kharbanda, P.S. (2016). Valproic Acid: A Summary of Indian Epilepsy Society-Consensus Document. International Journal of Epilepsy, 3(01), pp.028-032.
60. Mohamed THE, Alanazi AOZ, Alshammari TMF, Alshammari ANM, Alenezi OML, Alruwili WAO, Almatrafi SKF. (2020). Epilepsy in Saudi Arabia: Prevalence in Different Regions, Causes, Risk Factors, and Management: A Systematic Review.International Journal of Pharmaceutical and Phytopharmacological Research; 10(6):92-99.
61. Mohsen, F., Amir Hooshang, M., Naser Vahdati, M., Mohammad Hassanzadeh, K., Mahmood Reza, A., Naghmeh, M., Tamara, A. and Jamal, S. (2009). Therapeutic drug monitoring of valproic acid in patients with monotherapy at steady state.
62. Moseley, B., Bateman, L., Millichap, J.J., Wirrell, E. and Panayiotopoulos, C.P. (2013). Autonomic epileptic seizures, autonomic effects of seizures, and SUDEP. Epilepsy & Behavior, 26(3):375-385.
63. Muthaffar, O.Y., Almahmudi, S.M., Alrabghi, M.O., Mahfouz, M.M.B. and Alfawaz, N.S. (2021). Valproic acid for children below 2 years of age with epilepsy. Neurosciences Journal, 26(4), pp.357-365.
64. Neubauer BA, Gross S, Hahn A. (2008). Epilepsy in childhood and adolescence. Dtsch Arztebl Int.;105(17):319-328.
65. Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. (2010). Estimation of the burden of active and life‐time epilepsy: a meta‐analytic approach.
66. Epilepsia.;51(5):883-90.
67. Noebels J, Avoli M, Rogawski M, Olsen R, Delgado- Escueta A. (2012). Jasper’s Basic Mechanisms of the Epilepsies. Oxford University Press;466–70.
68. Nunes, V.D., Sawyer, L., Neilson, J., Sarri, G. and Cross, J.H. (2012). Diagnosis and management of the epilepsies in adults and children: summary of updated NICE guidance. Bmj, 344.
69. Patsalos, P.N., Berry, D.J., Bourgeois, B.F., Cloyd, J.C., Glauser, T.A., Johannessen, S.I., Leppik, I.E., Tomson, T. and Perucca, E. (2008). Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic
70. Strategies. Epilepsia, 49(7), pp.1239-1276.
71. Perucca P, Carter J, Vahle V, Gilliam FG. (2009). Adverse antiepileptic drug effects: toward a clinically and neurobiologically relevant taxonomy. Neurology ;72(14):1223–9, 3.
72. Rabie, F.M., Al Asmari, A.H., Al-Barak, S.A., Al-Rashed, F.M. and Mare, N. (2016).
73. Prevalence and Determinants of Epilepsy among School Children in Aseer RegionKSA. Journal of Education and Practice, 7(21), pp.149-153.
74. Raspall-Chaure M, Neville BG, Scott RC. (2008). The medical management of the epilepsies in children: conceptual and practical considerations. Lancet Neurol;7(1):57–69.
75. Reith DM, Andrews J, McLaughlin D. (2001). Valproic acid has temporal variability in urinary clearance of metabolites. Chronobiol Int; 18:123-129.
76. Romoli, M., Mazzocchetti, P., D'Alonzo, R., Siliquini, S., Rinaldi, V.E., Verrotti, A., Calabresi, P. and Costa, C. (2019). Valproic acid and epilepsy: from molecular mechanisms to clinical evidences. Current neuropharmacology, 17(10), pp.926-946.
77. Ropper AH, Adams RD, Victor M, Samuels MA,(2009). Ropper AH. Adams and Victor’s principles of neurology. 9th ed. New York: McGraw-Hill Medical.
78. Rudzinski, L.A., J. Jerry and J.J. Shih. (2013). New drug classes for the treatment of partial onset epilepsy: Focus on perampanel. Therapeutic Clin. Risk Manag., 9: 285-293. Saad, K. (2014). Childhood epilepsy: an update on diagnosis and management. American Journal of Neuroscience, 5(2), pp.36-51.
79. Scott RA, Lhatoo SD, Sander JW. (2001).The treatment of epilepsy in developing countries: where do we go from here? Bulletin of the World Health Organization ;79:344–51.
80. Shaikh, A.S., Liu, H., Li, Y., Cao, L. and Guo, R. (2018). Therapeutic drug monitoring of valproic acid. Pakistan Journal of Pharmaceutical Sciences, 31(4 SI), pp.1773-1777.
81. Sharma, S., Gulati, S., Kabra, M., Kalra, V., Vasisht, S. and Gupta, Y.K. (2011). Blood ammonia levels in epileptic children on 2 dose ranges of valproic acid monotherapy: a cross-sectional study. Journal of Child Neurology, 26(1), pp.109-112.
82. Star, K., Edwards, I.R. and Choonara, I. (2014). Valproic acid and fatalities in children: a review of individual case safety reports in VigiBase. PLoS One, 9(10), p.e108970.
83. Stefan, H. and Theodore, W.H. eds. (2012). Epilepsy, Part I: Basic Principles and Diagnosis.
84. Stephani, C. and Koubeissi, M. (2017). Hypercognitive seizures− Proposal of a new term for the phenomenon forced thinking in epilepsy. Epilepsy Research, 134:.63-71.
85. Sven C, van Dijkman, Ricardo Alvarez-Jimenez , et al. (2016). Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go. Expert Opin Drug Metab Toxicol;12:101143–1156.
86. Tomson T, Battino D, Perucca E. (2016). Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug. Lancet Neurol; 15: 210-218.
87. Tamber, M.S. and J.M. Mountz. (2012). Advances in the diagnosis and treatment of epilepsy. Seminars Nuclear Med., 42: 371-386.
88. Uijl SG, Uiterwaal CS, Aldenkamp AP, Keizer K. (2009). Adjustment of treatment increases quality of life in patients with epilepsy: a randomized controlled pragmatic trial. Eur J Neurol;16 (11):1173–7.
89. Vignoli, A., Oggioni, G., De Maria, G., Peron, A., Savini, M.N., Zambrelli, E., Chiesa, V., La Briola, F., Turner, K. and Canevini, M.P. (2017). Lennox–Gastaut syndrome in adulthood: Long-term clinical follow-up of 38 patients and analysis of their recorded seizures. Epilepsy & Behavior, 77: 73-78.
90. Villarreal, H.J.; Wilder, B.J.; Willmore, L.J.; Bauman, A.W. (1978). Hammond, E.J.; Bruni, J. Effect of valproic acid on spike and wave discharges in patients with absence seizures. Neurology, 28(9Pt 1), 886-891.
91. Wagner JL, Mueller M, Kellermann T, et al. (2019). Vulnerabilities to antiepileptic drug (AED) side effects in youth with epilepsy. Epilepsy Behav;97:22–8.
92. Wang Y, Hu W, Li Z. (2020). Influence of age and co-medication on the concentration and efficacy of valproic acid in Chinese epilepsy children. Pak J Pharm Sci; 33: 537-542.